1. Field of the Invention
The present invention relates to chiral phosphine ligands for asymmetric catalysis.
2. Description of Related Arts
Molecular chirality plays a very important role in science and technology. The biological activities of many pharmaceuticals, fragrances, food additives and agrochemicals are often associated with their absolute molecular configuration. While one enantiomer gives a desired biological function through interactions with natural binding sites, another enantiomer usually does not have the same function and sometime has deleterious side effects.
The sale of enantiomerically pure pharmaceuticals was about $61 billion in 1995, about 26 percent of the $240 billion total market for final formulation pharmaceuticals (Cannaesa, M. S. Symposium, Chiral ""97, Matrix, 1997; Cannarsa, M. J. Chemistry and Industry, 1996, May 20, page 374). There is a growing demand in the pharmaceutical and fine chemicals industries to develop cost-effective processes for the manufacture of single-enantiomeric products.
To meet this fascinating challenge, chemists have explored many approaches for acquiring enantiomerically pure compounds ranging from optical resolution and structural modification of naturally occurring chiral substances to asymmetric catalysis using synthetic chiral catalysts and enzymes. Among these methods, asymmetric catalysis is perhaps the most efficient because a small amount of a chiral catalyst can be used to produce a large quantity of a chiral target molecule. During the last two decades, great attention has been devoted to discovering new asymmetric catalysts and many commercial industrial processes have used asymmetric catalysis as the key step in the production of enantiomerically pure compounds. See (a) Morrison, J. D., Ed. Asymmetric Synthesis Academic Press: New York, 1985, Vol. 5; (b) Bosnich, B., Ed. Asymmetric Catalysis Martinus Nijhoff Publishers: Dordrecht, The Netherlands, 1986; (c) Brunner, H. Synthesis 1988, 645; (d) Noyori, R.; Kitamura, M. In Modern Synthetic Methods; Scheffold, R., Ed.; Springer-Verlag: Berlin Hedelberg, 1989, Vol. 5, p 115: (f) Nugent, W. A., RajanBabu, T. V., Burk, M. J. Science 1993, 259, 479; (g) Ojima, I., Ed. Catalytic Asymmetric Synthesis, VCH: New York, 1993; and (h) Noyori, R. Asymmetric Catalysis In Organic Synthesis, John Wiley and Sons, Inc: New York, 1994.
In order to develop efficient synthetic methods that have a real impact in the pharmaceutical industry, it is useful to categorize the chiral building blocks according to their functionality and analyze what is needed in each area. A recent survey by Technology Catalysts International shows that amino acid derivatives, chiral amines, and chiral alcohols comprise over 40 percent of developmental enantiomerically pure pharmaceuticals. Asymmetric hydrogenation plays a dominant role in the manufacture of enantiomerically pure compounds. Major pharmaceutical and fine chemical companies have devoted significant effort in developing and commercializing asymmetric hydrogenation technology. The key element of the research is developing chiral phosphine ligands to increase reaction selectivity and activity.
In fact, asymmetric hydrogenation accounts for major part of all asymmetric synthesis on a commercial scale. Many important advances have been achieved based on the discovery of structurally different chiral phosphine motifs. Some dramatic examples of industrial applications of asymmetric synthesis include Monsanto""s L-DOPA synthesis (asymmetric hydrogenation of a dehydroamino acid, 94% ee, 20,000 turnovers with a Rh-DIPAMP complex) (Knowles, W. S., Acc. Chem. Res. 1983, 16, 106), Takasago""s L-menthol synthesis (asymmetric isomerization, 98% ee, 300,000 turnovers with a Rh-BINAP complex) (Noyori, R. Science 1990, 248, 1194; Noyori, R. et al., Acc. Chem. Res. 1990, 23, 345) and Ciba-Geigy""s (S)-Metolachlor synthesis (asymmetric hydrogenation of an imine, 80% ee, 1,000,000 turnovers with an Ir-ferrocenyl phosphine complex) (see Proceeding of the Conference on Catalysis of Organic Reactions, Spindler, F., et al., Altanta, 1996; Chem. Ind. (Dekker), 1996, 63; Tongni, A. Angew. Chem. lnt. Ed. Engl. 1996, 356, 14575).
Chiral ligands for transition metal-catalyzed reactions play a critical role in asymmetric catalysis. Not only the enantioselectivity depends on the framework of chiral ligands; reactivities can often be altered by changing the steric and electronic structure of the ligands. Since small changes in the ligand can influence the (delta)(delta)G of the rate determining step, it is very hard to predict which ligand can be effective for any particular reaction or substrate. The majority of breakthroughs in asymmetric catalysis have come from the empirical match of the right ligands with the right transition metals. Perusal of the literature shows that over 100 chiral phosphines were investigated to discover the original L-Dopa asymmetric hydrogenation catalyst.
While ideas based on conformational analysis or steric and electronic properties are useful for ligand design and for generating working hypotheses, overemphasis on these ideas can potentially misguide and hinder the development of truly efficient ligands. Creation of a new ligand motif and fine-tuning (trouble-shooting) established chiral ligand systems are equally important in asymmetric catalysis. For example, many chiral diphosphines have similar chemical structures (e.g., chelating bis-diphenyl phosphine with chiral backbones), yet most of these ligands have different profiles in terms of enantioselectivity and activity for transition metal-catalyzed reactions. Understanding of the subtle changes which makes a particular ligand more effective for a certain reaction than another similar ligand is the intellectual frontier of current study in asymmetric catalysis. In the process of creating low molecular weight catalysts with enzymatic properties, the invention of effective chiral ligands is analogous to generating new enzyme frameworks.
The development of chiral phosphines has had a profound impact in the field of asymmetric catalysis. FIG. 1 shows several important chiral phosphines studied during the last three decades. Knowles"" DIPAMP (Knowles, W. S. et al., J. Chem. Soc., Chem. Commun. 1972, 10; Vineyard, B. D. et al., J. Am. Chem. Soc. 1977, 99, 5946) and Kagan""s Diop (Kagan, H. B.; Dang, T.-P. J. Am. Chem. Soc. 1972, 94, 6429) ligands were reported for Rh (I) catalyzed asymmetric hydrogenation at about the same time. The great success in asymmetric hydrogenation of a-acylaminoacrylic acids stimulated continuing research on new chiral phosphine ligands.
Various bidentate chiral diphosphines such as Chiraphos (Fryzuk, M. D. et al., J. Am. Chem. Soc. 1977, 99, 6262), BPPM (Achiwa, K. J. Am. Chem. Soc. 1976, 98, 8265; Ojima, I., Tetrahedron Lett. 1980, 21, 1051), DegPhos (Nagel, U., et al., Chem. Ber. 1986, 119, 3326) and ferrocenyl chiral phosphines (Hayashi, T. et al., Fundamental Research in Homogeneous Catalysis, Ishii, Y. et al., (Eds.) Plenum: New York, 1978; Vol. 2, p 159; Hayashi, T., et al., Acc.. Chem. Res. 1982, 15, 395; Ito, Y., et al., Am. Chem. Soc. 1986, 108, 6405) were discovered in both academic labs and in industry. Two benchmark ligands come out of extensive ligand studies: BINAP (Miyashita, A., et al., J. Am. Chem. Soc. 1980, 102, 7932; Miyashita, A., et al., Tetrahedron 1984, 40, 1245; Takaya, H., et al., J. Org. Chem. 1986, 51, 629; Takaya, H., et al., Org. Synth. 1988, 67, 20) in the early 80""s is one of the most frequently used bidentate chiral phosphines, and DuPhos (Burk, M. J., et al., Organometallics 1990, 9, 2653; Burk, M. J. J. Am. Chem. Soc. 1991, 113, 8518; Burk, M. J., et al., J. Am. Chem. Soc. 993, 115, 10125) in the early 90""s has also shown impressive enantioselectivities.
The Rh, Ru and Ir complexes of these ligands have been used as catalysts for asymmetric hydrogenation of olefins, ketones and imines. These ligands are also useful for other asymmetric reactions such as isomerization, hydroacylation, Heck reaction, and Grignard coupling. However, there are still a variety of reactions in which only modest enantioselectivity has been achieved with these ligands, and substrate scope is limited both for hydrogenation and for other reactions. Complementary classes of chiral ligands are needed.
Due to the critical role of chiral ligands in reaction activity and selectivity, many new phosphine ligands were invented in the 90""s. The major feature of the new chiral phosphine ligands is their structural diversity where different structural motif is created, ligand complexity increases, and the steric and electronic properties of ligands are more tunable. Some of these ligands include monodentate chiral phosphines (MOP) (Hayashi, T. J. Syhth. Org. Chem., Jpn. 1994, 901; Uozumi, Y. et al., J. Am. Chem. Soc. 1991, 113, 9887; Hayashi, T., et al., Pure and Appl. Chem. 1992, 64, 1911), ferrocenyl phosphine bearing two different phosphine groups (Togni, supra), Trost""s chiral bisphosphines (Trost, B. M., et al., Chem. Rev. 199 , 96, 395), mixed N-P ligands (Pfaltz, A. Acc. Chem. Res. 1993, 26, 339 and Helmchen), Trans diphosphines (TRAP) (Sawamura, M., et al., J. Am. Chem. Soc. 1996, 118, 3309; Sawamura, M., et al., Angew. Chem. Int. Ed.Engl. 1994, 33, 111) and phosphine-phosphite ligand (BINAPHOS) (Nozaki, K., et al., J. Am. Chem. Soc. 1995, 117, 9911; Sakai, N., et al., J. Am. Chem. Soc. 1993, 115, 7033). These new ligands are effective for several asymmetric reactions: hydrosilylation, hydrogenation of imines, allylic alkylation, Michael addition and hydroformylation. It is important to note that many basic catalytic reactions have been discovered and extensively studied for all these important asymmetric reactions. Even with a good understanding of the basic reaction mechanism, discovering effective chiral phosphine ligands for transition metal-catalyzed reactions is still a tremendous challenge.
The development of chiral ligands to control catalytic activity and enantioselectivity remains as one of the most exciting and challenging subjects in research on catalytic asymmetric synthesis. Most chiral phosphines prepared so far are bisphosphines. The bidentate chelation of the ligand is effective for many asymmetric reactions. On the other hand, only a limited number of monodentate chiral phosphines have been prepared and studied. The general view is that monodentate chiral phosphines have little practical utility. However, there are many transition metal-catalyzed reactions where metal complexes with bisphosphines are not effective because of low activity and selectivity and therefore chiral monophosphines are required. This situation is particularly true for certain Ni and Pd-catalyzed reactions. So far, the most well-studied monodentate phosphines are Hayashi""s MOP, 2-(diphenylphosphino)-2xe2x80x2-methoxy-1,1xe2x80x2-binaphthyl and its analogs. Several effective asymmetric reactions were achieved with Pd-MOP catalyst: asymmetric hydrosilylation of alkyl-substituted terminal olefins, asymmetric 1,4-hydroboration of 1,3-enynes, and asymmetric reduction of allylic esters with formic acid.
While high selectivities were obtained in many reactions using some of the chiral diphosphine ligands in FIG. 1, there are many reactions where these ligands are not very efficient in terms of activity and selectivity. There are many disadvantages associated with these ligands, which hinder their applications. For DIPAMP, the phosphine chiral center is difficult to make. This ligand is only useful for limited application in asymmetric hydrogenation. For BPPM, DIOP, and Skewphos, the methylene group in the ligands causes conformational flexibility and enantioselectivities are moderate for many catalytic asymmetric reactions. DEGPHOS and CHIRAPHOS coordinate transition metals in five-membered ring. The chiral environment created by the phenyl groups is not close to the substrates and enantioselectivities are moderate for many reactions. BINAP, DuPhos and BPE ligands are good for many asymmetric reactions. However, the rotation of the arylxe2x80x94aryl bond makes BINAP very flexible. The flexibility is an inherent limitation in the use of phosphine ligand. Furthermore, because the phosphine of BINAP contains three adjacent aryl groups, it is less electron-donating than a phosphine that has less aryl groups. This is an important factor influencing reaction rates. For hydrogenation reactions, electron-donating phosphines are more active. For the more electron-donating DUPHOS and PBE ligands, the five-membered ring adjacent to the phosphines is flexible.
Chiral bidentate phosphites with a rigid backbone are rare in the literature. The strategy of rigidifying chiral phosphines can be applied to make new chiral phosphites. An example is to rigidify the Union Carbide chiral bisphosphite ligands with a BICP diol. This will be useful to develop asymmetric hydroformylation reactions. There are only few reports about asymmetric catalysis with transition metal complexes with chiral monophosphines. Bulky and conformationally rigid chiral monophosphines as well as their hemilabile version of these ligands are made for asymmetric catalytic reactions.
There remains a need to develop and apply chiral phosphine ligands to a variety of asymmetric reactions such as hydrogenation, hydride transfer reaction, hydrosilylation, hydroboration, hydrovinylation, olefin metathesis, hydroformylation, hydrocarboxylation, allylic alkylation, cyclopropanation, Diels-Alder reaction, Aldol reaction, Heck reaction and Michael addition are explored based on these innovative ligand systems. Success would lead to efficient and practical methods for producing important chiral drugs for anti-hypertensive, antihistamine, cardiovascular, and central nervous system therapies.
Much effort has been devoted to the development of efficient asymmetric synthetic methods for the preparation of enantiomerically enriched compounds. Among various methods for the enantiomerically selective synthesis of chiral organic compounds from prochiral precursors, enantioselective catalytic hydrogenation of dehydro precursors has been extensively developed. In fact, asymmetric hydrogenation is one of the most practical methods in asymmetric synthesis, accounting for 70% of all procedures used on a commercial scale. However, most asymmetric catalytic hydrogenation systems only hydrogenate electron deficient olefins with high enantioselectivity and high reactivity. In contrast, electron-rich olefins, such as simple enamides and enolates, are generally poor substrates for asymmetric hydrogenation with most known systems (T. Monmoto, M., et al., Chem. Pharm. Bull. 1992, 40, 2894; H. B. Kagan, et al., J. Organomet. Chem. 1975, 90, 353; D. Sinou, et al., J. Organomet. Chem. 1976, 114, 325; highly enantioselective hydrogenation of enamines was achieved using a chiral titanocene catalyst: N. E. Lee, et al., J. Am. Chem. Soc., 1994, 116, 5985; J. M. Brown, et al., J. Chem. Soc. Perkin II 1982, 489; K. E. Koenig, et al., J. Org. Chem. 1980, 45, 2362; R. Selke, et al., J. Mol. Catal. 1986, 37, 213; M. D. Fryzuk, et al., J. Am. Chem. Soc. 1978, 100, 5491; K. E. Koenig in Asymmtric Synthesis; Vol 5 (Ed: J. D. Morrison), Academic Press, New York, 1985, Chapter 3). Since enamides and enolates upon asymmetric hydrogenation can be converted to enantiomerically pure amines and alcohols, it would be extremely desirable to have a general and efficient method for this transformation. It was difficult to synthesize isomerically pure enamides using older methods. Recently, Burk and coworkers have reported that Rh-complexes bearing the electron-rich DuPhos and BPE type ligands were efficient catalysts for the asymmetric hydrogenation of enamides and enolates (M. J. Burk, et al., J. Am. Chem. Soc. 1996, 118, 5142; M. J. Burk, et al., J. Am. Chem. Soc. 1991, 113, 8518). They reported that analogous Rh-chiral bisphosphines bearing diphenylphosphino groups (e.g., BINAP, DIOP and CHIRAPHOS) led to significantly lower enantioselectivities in the reduction of enamides ( less than 60% ee).
We have been interested in elucidating the steric and electronic effects of various diphenylphosphino-bearing chiral ligands in asymmetric hydrogenation processes. Recently a new chiral 1,4-bisphosphine, (2R,2xe2x80x2R)-bis(diphenylphosphino)-(1R,1xe2x80x2R)-dicyclopentane ((R,R)-BICP), was reported from our laboratory as an excellent ligand for the Rh-catalyzed asymmetric hydrogenation of dehydroamino acids (G. Zhu, et al., J. Am. Chem. Soc. 1997, 119, 1799). In this new ligand, four stereogenic centers are introduced in a conformationally rigid bicyclic backbone, which is fundamentally different from either axially dissymmetric BINAP or bisphosphines with two stereogenic centers. Among chiral bisphosphines with diphenylphosphino groups, the BICP ligand gives high enantioselectivity for the rhodium-catalyzed asymmetric hydrogenation of simple enamides. 
One aspect of the invention is in providing a chiral compound selected from L1, L2, L3, and L4 and corresponding enantiomers: 
wherein m ranges from 1 to 8 to form a ring, wherein the ring may be unsubstituted or substituted and may be part of a fused ring; R4 is unsubstituted or substituted aryl or alkyl; 
wherein each R6 independently represents two substituents which are independently C1-C5 alkyl or alkoxy groups, each meta to the bond joining the phenyl rings; 
wherein s ranges from 1 to 4; t ranges from 1 to 4; R9 is unsubstituted or substituted aryl or alkyl; R10 is hydrogen, or one or more unsubstituted or substituted aryl or alkyl groups; R12 is one or more unsubstituted or substituted aryl or alkyl groups; and Ar1 is unsubstituted or substituted aryl.
Another aspect of the invention is in providing a catalyst comprising one of the above compounds at an optical purity of at least 85% ee and a transition metal.
The present invention further provides a process comprising subjecting a substrate to an asymmetric reaction in the presence of such a catalyst, wherein said asymmetric reaction is a hydrogenation, hydride transfer, hydrosilylation, hydroboration, hydrovinylation, olefin metathesis, hydroformylation, hydrocarboxylation, allylic alkylation, cyclopropanation, Diels-Alder, Aldol, Heck, [m+n] cycloaddition, or Michael addition reaction.
The ligands of the invention in FIG. 2 have at least four chiral centers in their backbones and can form chelating rings with many transition metals.
BICP has four stereogenic carbon centers in the backbone. This structure is fundamentally different from either axially dissymmetric BINAP or bisphosphines with two stereogenic carbon centers in their backbone such as Chiraphos, DIOP and BPPM.
The rigid, fused phosphabicyclo[2.2.1]heptane structure in ligands such as PennPhos is a new structural motif.
There are many transition metal catalyzed reactions that do not work with chelating bidentate ligands. Efficient chiral monophosphines of the present invention are clearly needed.
The availability of chiral phosphines is always a worthwhile consideration for practical applications of the chemistry. Early phosphine systems such as Diop, DegPhos and BPPM relied on chiral pool species for the origin of ligand chirality. This approach necessarily permits only limited structural diversity in the ligands. Other chiral phosphine ligands, e.g., DIPAMP, BINAP and DuPhos, were made by chiral resolution and asymmetric synthesis. Ligand synthesis is often a challenging synthetic task. We choose our ligand synthesis routes based on readily available starting materials such as cyclopentanone and paraxylene.
Fine-tuning the steric and electronic properties of chiral phosphine ligands is important. With the chiral phosphabicyclo[2.2.1]heptane systems, varying alkyl substituents is easy and this variation will provide a different steric environment around the transition metal. For the diphenylphosphine systems bearing chiral backbones, electronic properties can be altered by substituting phenyl with other aromatic groups. Finally, changing the chiral backbones of the phosphines adds another dimension to varying steric and electronic properties. The bite angle P-M-P is different from one ligand to another.
Accordingly, an advantage of the invention is to provide new chiral ligand structural motifs. A further advantage of the invention is to provide new chiral ligand structural motifs allowing greater ligand structural diversity.
A further advantage of the invention is to provide new chiral monodentate phosphine ligands.
A further advantage of the invention is to provide methods of carrying out asymmetric synthesis using chiral phosphine and phosphite ligands.
A further advantage of the invention is to provide methods for efficient asymmetric carbon-hydrogen bond formation.
A further advantage of the invention is a method of performing the asymmetric hydrogenation of enamides and cyclic enamides using chiral catalysts.
A further advantage of the invention is to provide methods for efficient asymmetric hydrogenation of imines, enol acetates, enol ethers, or alkenes.
A further advantage of the invention is to provide methods for efficient asymmetric carbonxe2x80x94carbon bond formation.
A further advantage of the invention is to provide methods for efficient asymmetric hydroformylation or hydrovinylation.
Additional advantages of the invention will be set forth in part in the description that follows, and in part will be obvious from the description, or may be learned by practice of the invention. The objects and advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. Both the foregoing general description and the following detailed description of the invention are exemplary and explanatory only and are not necessarily restrictive of the claimed invention.